Search PubMed⌕ Search

Biomedical subjects

L Bell

Publications and source records attributed to L Bell.

At least 55 records · Page 3Linked to original sources
PubMed1992

An endosomal-lysosomal pathway for degradation of amyloid precursor protein.

We previously reported evidence for a lysosomal degradative pathway for APP and C-terminal fragments thereof, based on Western and immunocytochemical analysis of drug-treated cells. Here, we verify the existence of a lysosomal degradative pathway for APP using pulse chase immunoprecipitation analysis of drug-treated cells and fibroblasts with and without a known lysosomal hydrolase targeting defect. The results are consistent with the hypothesis that part or all of the beta-protein domain of APP is normally degraded by lysosomes. A mechanism for beta-protein deposition based on this data is hypothesized.

Amyloid beta-Protein Precursor↗
PubMed1992

Modulation of vascular cell behavior by transforming growth factors beta.

The vascular cell responses to the type 1, 2, and 3 isoforms of transforming growth factor-beta (TGF-beta 1, TGF-beta 2, TGF-beta 3) were studied using bovine aortic endothelial (BAECs) and smooth muscle cells (BASMC3) as well as rat epididymal fat pad microvascular endothelia (RFCs). Three distinct bioassays indicated that TGF-beta elicits results that do not differ significantly from those of the TGF-beta 1 isoform in all three cell populations. These assays are: inhibition of proliferation, cell migration, and neovascularization. By contrast the cellular responses to TGF-beta 1 and TGF-beta 3 differed from those to TGF-beta 2. Three distinct receptor assays revealed the presence of type I and type II TGF-beta 1 cell surface binding proteins on BAECs, BASMCs, and RFCs. Experimentation to decipher cell surface binding by the different isoforms revealed that iodinated TGF-beta 1 bound to the surface of all three vascular cell types can be competed off in similar fashion by either TGF-beta 1 or TGF-beta 3; however, competition with TGF-beta 2 produced unique binding profiles dependent on the cell type examined. The ratios of type I to type II TGF-beta receptors in these three vascular cell types vary from 1:1 in BAECs to 1.5:1 in RFCs to 3:1 in BASMCs and can be correlated with the differences noted in cellular responses to TGF-beta 1 and TGF-beta 2 in proliferation, migration, and in vitro angiogenic assays.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Autocrine angiotensin system regulation of bovine aortic endothelial cell migration and plasminogen activator involves modulation of proto-oncogene pp60c-src expression.

Rapid endothelial cell migration and inhibition of thrombosis are critical for the resolution of denudation injuries to the vessel wall. Inhibition of the endothelial cell autocrine angiotensin system, with either the angiotensin-converting enzyme inhibitor lisinopril or the angiotensin II receptor antagonist sar1, ile8-angiotensin II, leads to increased endothelial cell migration and urokinase-like plasminogen activator (u-PA) activity (Bell, L., and J. A. Madri. 1990. Am. J. Pathol. 137:7-12). Inhibition of the autocrine angiotensin system with the converting-enzyme inhibitor or the receptor antagonist also leads to increased expression of the proto-oncogene c-src: pp60c-src mRNA increased 7-11-fold, c-src protein 3-fold, and c-src kinase activity 2-3-fold. Endothelial cell expression of c-src was constitutively elevated after stable infection with a retroviral vector containing the c-src coding sequence. Constitutively increased c-src kinase activity reconstituted the increases in migration and u-PA observed with angiotensin system interruption. Antisera to bovine u-PA blocked the increase in migration associated with increased c-src expression. These data suggest that increases in endothelial cell migration and plasminogen activator after angiotensin system inhibition are at least partially pp60c-src mediated. Elevated c-src expression with angiotensin system inhibition may act to enhance intimal wound closure and to reduce luminal thrombogenicity in vivo.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1992

Cholesterol-lowering effects of calcium carbonate in patients with mild to moderate hypercholesterolemia.

BACKGROUND: In recent years, several authors have noted that oral calcium treatment was associated with a reduction in serum cholesterol level. METHODS: Calcium carbonate was examined for its ability to lower serum cholesterol levels in hypercholesterolemic patients. Fifty-six patients with mild to moderate hypercholesterolemia were examined in this randomized, double-blind, placebo-controlled crossover study. Patients were treated with a low-fat, low-cholesterol diet targeted at the American Heart Association Step-1 diet for 8 weeks before and while receiving placebo or calcium carbonate (9.98 mmol [400 mg] of elemental calcium) three times daily with meals for 6 weeks. Patients were then crossed over to the alternate treatment for an additional 6-week period. RESULTS: Compared with placebo, calcium carbonate achieved a 4.4% reduction in the low-density lipoprotein cholesterol level, and a 4.1% increase in the high-density lipoprotein cholesterol level. The ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol significantly decreased by 6.5% with calcium carbonate treatment. Calcium carbonate treatment did not significantly affect blood pressure or serum levels of triglycerides, lipoprotein Apo B, or calcium. Relative urinary saturation ratios of calcium oxalate levels were unchanged during calcium carbonate therapy. Compliance with diet and treatment was excellent and no significant adverse effects were noted. CONCLUSIONS: Thus, calcium carbonate was a modestly effective and well-tolerated adjunct to diet in the management of mild to moderate hypercholesterolemia in this clinical study.

Adult↗
PubMed1991

Role of pertussis toxin-sensitive guanosine triphosphate-binding proteins in the response of erythroblasts to erythropoietin.

Human progenitor-derived erythroblasts have been recently shown to respond to erythropoietin (Epo) with an increase in intracellular free calcium concentration [Cac]. To explore the role of guanosine triphosphate (GTP)-binding proteins in mediating the rise in [Cac], single day 10 erythroid burst forming unit (BFU-E)-derived erythroblasts loaded with Fura-2 were pretreated with pertussis toxin (PT), stimulated with Epo, and [Cac] measured over 18 minutes with fluorescence microscopy coupled to digital video imaging. The [Cac] increase in day 10 erythroblasts stimulated with Epo was blocked by pretreatment with PT in a dose-dependent manner but not by heat-inactivated PT. These observations provided strong evidence that a PT-sensitive GTP-binding protein is involved. To further characterize the GTP-binding protein, day 10 erythroblast membrane preparations were solubilized, electrophoresed, and immunoblotted with antibodies specific for the known PT-sensitive G-protein subunits: the three subtypes of Gia (1,2, and 3) and Goa, Gia1 or Gia3 and Gia2 were identified but no Goa was found. To examine the influence of Epo on adenylate cyclase activity, day 10 erythroblasts were initially treated with Epo, isolated membrane preparations made, and cyclic adenosine monophosphate (cAMP) production by adenylate cyclase in membrane preparations in the presence of theophylline measured. Epo did not inhibit but significantly stimulated adenylate cyclase activity. However, the mechanism of increase of [Cac] appears to be independent of adenylate cyclase stimulation because treatment of erythroblasts with the cell-permeant dibutyryl cAMP failed to increase [Cac]. In summary, pertussis toxin blocks the increase in [Cac] in erythroblasts after Epo stimulation suggesting that this response is mediated through a pertussis toxin-sensitive GTP-binding protein. Candidate PT-sensitive GTP-binding proteins identified on day 10 erythroblasts were Gia 1, 2, or 3, but not Goa.

Adenylate Cyclase Toxin↗
PubMed1991

Effects of soluble factors and extracellular matrix components on vascular cell behavior in vitro and in vivo: models of de-endothelialization and repair.

Vessel walls are comprised of several different cell populations residing in and on complex extracellular matrices. Each of the vascular cell types has diverse and sometimes unique functions and morphologies, and each has roles in repair processes following injury. Large vessel endothelial cells are known to respond to denudation injury by sheet migration and proliferation. This is in contrast to the migration through soft tissues with tube formation and subsequent lumen formation exhibited by microvascular endothelial cells in response to injury. Vascular smooth muscle cells of larger vessels respond to injury by migration from the arterial media into the intima, proliferation, and matrix biosynthesis, ultimately causing intimal thickening. Both these cell types exhibit "dysfunctional" phenotypes during their responses to injury. Microvascular cell responses to injury, while extremely variable, are less well documented. Specifically, responses to injury by microvascular endothelial vascular cells appear to be modulated, in part, by the composition and organization of the surrounding matrix as well as by the various soluble factors and cytokines found at sites of injury, suggesting that the extracellular matrix and soluble factors modulate each other's effects on local vascular cell populations following injury.

Animals↗
PubMed1991

Asynchronous development of the rat colon.

Mucosal ridge and fold formation, apoptosis and the occurrence of secondary lumina within the epithelium are morphological features associated with the development of the colon. These processes, however, do not occur synchronously in the various segments of the colon. In the caecum and ascending colon of the rat, fold formation, apoptosis and secondary lumina result in the development of villi by day 22 after conception, and by postnatal day 3 in the transverse colon. These villi persist in the rat colon until approximately postnatal day 10. The presence of colonic villi may be correlated with the increased food intake and fluid absorption during this early postnatal period. Villus formation does not take place in the developing descending colon.

Animals↗
PubMed1991

Chronic fibrosing pancreatitis in a 12-year-old female.

Recurrent abdominal pain in an adolescent population is a frequent complaint. However, diseases of the pancreas, and especially chronic pancreatitis, in this age group are extremely uncommon. One type of pancreatitis, fibrosing pancreatitis, has been reported in only 14 previous pediatric patients, five of whom were over 12 years of age. We report an additional 12-year-old female with this condition. This case serves to remind us that fibrosing pancreatitis needs to be considered in any adolescent patient with chronic abdominal pain, recurrent vomiting, weight loss, steatorrhea, and painless obstructive jaundice.

Abdominal Pain↗
PubMed1991

Influence of alpha-adrenergic receptor stimulation on splanchnic intravascular volume in conscious humans.

The influence of selective alpha-adrenergic receptor stimulation on total splanchnic intravascular volume and blood volume in individual splanchnic organs in humans has not been previously examined. The present study employed a previously validated quantitative radionuclide imaging technique, involving a gamma camera and Tc-99m labeled erythrocytes, to measure changes in total splanchnic, hepatic, splenic, and extrahepatosplenic volume during a 20-minute phenylephrine infusion (30-120 micrograms min-1 iv). Changes in total splanchnic volume were estimated from changes in total splanchnic radioactivity, blood radioactivity, and estimated in vivo tissue attenuation. Radionuclide-estimated total splanchnic volume increased 477 +/- 96 ml (P less than 0.0003) at the end of phenylephrine infusion. Hepatic volume increased 25 +/- 5% (P less than 0.0003), splenic volume decreased 46 +/- 7% (P less than 0.0003), and extrahepatosplenic volume decreased 15 +/- 2% (P less than 0.0003). Systolic and diastolic arterial pressures increased from 119 +/- 4 to 138 +/- 5 mmHg (P less than 0.0003) and from 83 +/- 1 to 96 +/- 2 mmHg (P less than 0.0003), respectively. Heart rate decreased from 62 +/- 2 to 51 +/- 3 bpm (P less than 0.0003). Thus, in man, selective alpha-adrenergic receptor stimulation is associated with an increase in splanchnic intravascular volume that is due to an increase in hepatic volume and occurs despite decreases in splenic and extrahepatosplenic volumes. This increase in total splanchnic volume would be associated with a decrease in venous return from the splanchnic vasculature to the right heart which would act to decrease cardiac output.

Adult↗
PubMed1991

Hemodynamic effects of 1:2 ECG-coupled jet ventilation in the dog. A comparison with other modes.

In 16 closed-chest dogs the hemodynamics of ECG-coupled jet ventilation (JV) with frequencies of 1:1 (one breath for each cardiac systole) and 1:2 (one breath for every other cardiac systole) were compared to noncoupled JV and intermittent positive-pressure ventilation (IPPV). Cardiac output was similar during 1:2 coupling (1.6 +/- 0.2 L/min) and IPPV (1.6 +/- 0.2 L/min) but decreased during 1:1 coupling (1.2 +/- 0.2 L/min) and noncoupled JV (1.3 +/- 0.2 L/min), p less than 0.05. During 1:2 coupling and IPPV, systemic arterial and transmural left atrial pressures were increased, and pulmonary artery, pericardial, and right atrial pressures were decreased in comparison to the other JV modes. Pulmonary blood volume was preserved during 1:2 coupling but decreased during 1:1 coupling and noncoupled JV. Coupling at 1:2 preserves output by maintaining left ventricular preload via a decrease in right atrial pressure and subsequent maintenance of systemic venous return.

Airway Resistance↗
PubMed1990

Spatiotemporal segregation of endothelial cell integrin and nonintegrin extracellular matrix-binding proteins during adhesion events.

Bovine aortic endothelial cell (BAEC) attachments to laminin, fibronectin, and fibrinogen are inhibited by soluble arginine-glycine-aspartate (RGD)-containing peptides, and YGRGDSP activity is responsive to titration of either soluble peptide or matrix protein. To assess the presence of RGD-dependent receptors, immunoprecipitation and immunoblotting studies were conducted and demonstrated integrin beta 1, beta 3, and associated alpha subunits as well as a beta 1 precursor. Immunofluorescence of BAECs plated on laminin, fibronectin, and fibrinogen reveals different matrix-binding specificities of each of these integrin subclasses. By 1 h after plating, organization of beta 1 integrin into fibrillar streaks is influenced by laminin and fibronectin, whereas beta 3 integrin punctate organization is influenced by fibrinogen and the integrin spatial distribution changes with time in culture. In contrast, the nonintegrin laminin-binding protein LB69 only organizes after cell-substrate contact is well established several hours after plating. Migration of BAECs is also mediated by both integrin and nonintegrin matrix-binding proteins. Specifically, BAEC migration on laminin is remarkably sensitive to RGD peptide inhibition, and, in its presence, beta 1 integrin organization dissipates and reorganizes into perinuclear vesicles. However, RGD peptides do not alter LB69 linear organization during migration. Similarly, agents that block LB69--e.g., antibodies to LB69 as well as YIGSR-NH2 peptide--do not inhibit attachment of nonmotile BAECs to laminin. However, both anti-LB69 and YIGSR-NH2 inhibit late adhesive events such as spreading. Accordingly, we propose that integrin and nonintegrin extracellular matrix-binding protein organizations in BAECs are both temporally and spatially segregated during attachment processes. High affinity nonintegrin interaction with matrix may create necessary stable contacts for longterm attachment, while lower affinity integrins may be important for initial cell adhesion as well as for transient contacts of motile BAECs.

Acid Phosphatase↗
PubMed1990

Alpha-adrenergic regulation of splanchnic volume and cardiac output in the dog.

The present study examined whether alpha-adrenergic stimulation causes a change in splanchnic intravascular volume in the anaesthetized animal with an intact circulation, which region(s) mediate the volume change, and whether the splanchnic volume change influences cardiac output. In order to ascertain that a radionuclide imaging technique could be used to assess total splanchnic volume changes, drugs known to increase or decrease splanchnic volume were infused on 21 occasions in eight dogs studied under conditions of selective perfusion and drainage of the splanchnic vasculature with erythrocytes labelled with 99Tcm and a gamma camera placed over the abdomen. For these 21 infusions, volume and radionuclide count changes were related: r greater than or equal to 0.90 (n = 20), r = 0.76 (n = 1). After ascertaining tissue attenuation and blood radioactivity in four of the animals, the standard error for a single estimate of the absolute volume change using the radionuclide technique was determined to be 75 ml. In six animals with intact circulations, phenylephrine (40-80 micrograms min-1) for 20 min was associated with an increase in cardiac output of 12 +/- 2% (P less than 0.001) and a decrease in total splanchnic volume estimated to be 431 +/- 95 ml (P less than 0.001). The splanchnic volume decrease was due entirely to decreases in splenic and intestinal volume. In eight eviscerated animals, cardiac output decreased by 30 +/- 2% (P less than 0.001) during phenylephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Influence of splanchnic intravascular volume changes on cardiac output during muscarinic receptor stimulation in the anaesthetized dog.

The direct influence of systemic muscarinic receptor stimulation on total splanchnic intravascular volume and the splanchnic organs responsible for the total splanchnic volume change associated with muscarinic receptor stimulation in the animal with an intact circulation are unknown. Furthermore, the subsequent effect of these volume changes on cardiac output is not known. Thus, acetylcholine was infused at 5 micrograms kg-1 min-1 in 25 anaesthetized dogs in which nicotinic blockade of the ganglia was achieved with mecamylamine, while total and regional splanchnic intravascular volume changes were determined with a radionuclide imaging technique. Total splanchnic volume decreased by 4.9 +/- 1.0% (P less than 0.0001), splenic volume decreased by 10.3 +/- 2.0% (P less than 0.0001), hepatic volume increased by 5.8 +/- 1.4% (P less than 0.01), extrahepatosplenic volume increased by 6.6 +/- 1.6% (P less than 0.01) and cardiac output increased from 1960 +/- 190 to 2290 +/- 230 ml min-1 (P less than 0.001). After splenectomy (n = 13), the hepatic and extrahepatosplenic volume increments were abolished, and the increase in cardiac output was not attenuated (1600 +/- 260 to 2040 +/- 370 ml min-1). After subsequent evisceration (n = 5), the cardiac output increment associated with acetylcholine was still not attenuated. Acetylcholine-associated splanchnic volume changes were abolished after muscarinic receptor blockade with atropine. Thus, muscarinic receptor stimulation causes a decrease in total splanchnic volume due entirely to a decrease in splenic volume. The splanchnic volume changes do not influence cardiac output.

Acetylcholine↗
PubMed1990

Quantitative radionuclide assessment of total pulmonary vascular volume changes.

Current techniques do not permit continuous and noninvasive assessments of changes in total pulmonary intravascular volume. Hence, the present study was undertaken to determine whether quantitative radionuclide imaging can be used to determine the direction and estimate the magnitude of total pulmonary vascular volume changes. The pulmonary circulation was separately perfused at a constant rate via the pulmonary artery and drained at a constant pressure via the left atrium in nine dogs. Changes in pulmonary intravascular volume were recorded as reciprocal changes in extracorporeal reservoir volume during phenylephrine or isoproterenol administration, a 20% increase in pulmonary artery flow or a 5 mmHg (1 mmHg = 133.32 Pa) decrease in left atrial pressure. Erythrocytes were labeled with technetium-99m and pulmonary volume changes were determined from tissue attenuation, blood radioactivity, and changes in total pulmonary radioactivity obtained with a gamma-camera. During each of the interventions, count changes correlated with volume changes (r greater than or equal to 0.75). The technique reliably detected volume changes as small as 10 mL. For all 531 individual pairs of radionuclide- and reservoir-determined volume changes, the correlation between reservoir-determined and radionuclide-estimated pulmonary intravascular volume changes was 0.87. The standard error of the radionuclide estimate was 21 mL. Hence, the present study demonstrates that quantitative radionuclide imaging can be used to continuously and noninvasively determine total pulmonary vascular volume changes.

Animals↗